N-substituted-7,8-dihydroxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolines and ethers and esters thereof

ABSTRACT

N-substituted cyclopentano[f]-1,2,3,4-tetrahydroisoquinolines of the formula ##SPC1## 
     Wherein R 1  and R 2  represent hydroxy, lower alkoxy, lower alkanoyloxy or aryl-lower alkanoyl groups, R 3  represents hydrogen or a lower alkyl group and R 4  represents a lower alkyl, arylcarbonyl, aryl-lower alkyl, benzhydryl-lower alkyl, lower alkanoyl, aryl-lower alkanoyl, benzhydryl-lower alkanoyl or benzhydrylcarbonyl group, and acid addition salts and quaternary ammonium salts thereof, and pharmaceutical compositions containing one or more of the compounds useful for lowering blood pressure in animals.

This invention relates to novel chemical compounds and their production.More particularly, this invention provides novel tetrahydroisoqinolines,processes for producing the compounds, and novel pharmaceuticalcompositions containing the compounds which are useful for effectingdesirable pharmacological activity in animals.

According to one aspect of the subject invention there is provided novelN-substituted cyclopentano[f]-1,2,3,4-tetrahydroisoquinolines of Formula1 ##SPC2##

Wherein R₁ and R₂ are hydroxy, lower alkoxy, lower alkanoyloxy oraryl-lower alkanoyloxy groups, R₃ is hydrogen or a lower alkyl group,and R₄ is a lower alkyl, arylcarbonyl, aryllower alkyl, benzhydryl-loweralkyl, lower alkanoyl, aryllower alkanoyl, benzhydryl-lower alkanoyl orbenzhydrylcarbonyl group, and acid addition salts and quaternaryammonium salts of those compounds which form such salts.

The term "lower alkyl" as used herein includes straight or branchedchain alkyl groups having 1 to 8, and advisably 1 to 6, carbon atomssuch as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,n-pentyl, isopentyl and n-hexyl.

The term "aryl" as used herein includes the phenyl group and phenylgroups containing one to three nuclear substituents selected from (1)lower alkoxy groups such as the methoxy and ethoxy groups, (2) loweralkyl groups such as the methyl and ethyl groups, (3) halo groupsincluding the chloro, bromo and fluoro groups, (4) the hydroxy group and(5) the amino group.

The term "benzhydryl" includes the benzhydryl group and benzhydrylgroups having, on one or both of the phenyl rings, one to three nuclearsubstituents selected from (1) lower alkoxy groups such as the methoxyand ethoxy groups, (2) lower alkyl groups such as the methyl and ethylgroups, (3) halo groups including the chloro, bromo and fluoro groups,(4) the hydroxy group and (5) the amino group.

The term "lower alkanoyl" includes saturated, monovalent groupsderivable from monocarboxylic acids, including straight and branchedchain groups having 1 to 8, and advisably 1 to 6, carbon atoms, such asformyl, acetyl, propionyl, α-methylpropionyl, butyryl and hexanoyl.

The term "lower alkanoyloxy' includes saturated monovalent groups frommonocarboxylic acids, including straight and branched groups, having 1to 8, and advisably 1 to 6, carbon atoms such as the formyloxy, acetoxy,propionyloxy and butyryloxy groups.

The N-substituted-7,8-dialkoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolines of Formula2 ##SPC3##

wherein R₅ and R₆ are lower alkoxy, and R₃ and R₄ have the assignedsignificance but R₄ has at least 2 carbons, all of which compounds comewithin Formula 1, can be produced by reacting a 7,8-di-loweralkoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline with an alkanoylhalide, an aryllower alkanoyl halide or a benzhydryl-lower alkanoylhalide to produce an ##EQU1## which is then reduced to the R₄-N-7,8-dialkoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline. Thisprocess can be represented as follows: ##SPC4## wherein R₃, R₄, R₅ andR₆ have the previously assigned significance, X is a reactive halo groupsuch as the bromo and chloro groups and --CH₂ -R₇ equals R₄.

Some of the tetrahydroisoquinolines which can be used as startingmaterials in the described process are7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,7,8-diethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,7,8-dipropoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline and7-methoxy-8-ethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.

Some alkanoyl halides and aryl-substituted alkanoyl halides which can beused in the first step of the process are acetyl chloride, propionylchloride, butyryl bromide, benzoyl chloride, p-methoxybenzoyl chloride,3,4-dimethoxybenzoyl chloride, 3,4,5-trimethoxybenzoyl chloride,diphenylacetyl chloride, diphenylpropionyl bromide,3,4-dimethoxyphenylacetyl chloride, 4-methylbenzoyl chloride,4-fluorophenylacetyl chloride and 3,4-diethoxybenzoyl chloride.

Reaction between the tetrahydroisoquinoline and alkanoyl halide, oraryl-substituted alkanoyl halide, to form the desired amide is readilyeffected by bringing the reactants together in an inert liquid reactionmedium, such as benzene or toluene, in the presence of an acid bindingagent, such as triethylamine. Heating of the mixture, such as at refluxtemperature, increases the reaction rate. After the reaction isterminated the amide reaction product can be isolated from the reactionmixture by conventional procedures.

Representative of the amides which can be produced as described from theappropriate reactants areN-acetyl-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-propionyl-7,8-diethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-(3,4-dimethoxybenzoyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-(3,4-dimethoxyphenylacetyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-(diphenylacetyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-(4-fluorophenylacetyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolineand N-(3,4,5-trimethoxybenzoyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.

The amides can be readily reduced chemically to the tertiary aminecompounds of Formula 2 where R₄ has at least 2 carbon atoms. Chemicalreduction of the amides can be effected by use of a suitable reducingagent, such as lithium aluminum hydride in anhydrous ether, at atemperature which increases the reaction rate, such as the refluxtemperature. The resulting tertiary amine can be recovered and isolatedas an acid addition salt using standard techniques.

Some of the tertiary amines which can be produced as described areN-ethyl-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-propyl-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-phenylethyl-7,8-diethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-benzyl-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-(3,4-dimethoxybenzyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-(3,4,5-trimethoxyphenylethyl)-7,8dimethoxycyclopentano[f]1,2,3,4-tetrahydroisoquinoline,N-(diphenylethyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-(4-fluorophenylethyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolineandN-(4-methylbenzyl)-7,8-diethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.

The compounds of Formula 2 in which R₄ is methyl can be prepared byreacting the secondary amines previously named above with formic acidand formaldehyde at an elevated temperature according to standardprocedures for methylating secondary amines to tertiary amines by thisprocess. Some of the tertiary amines which are produced in this way areN-methyl-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-methyl-7,8-diethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline andN-methyl-7,8-dipropoxycyclopentano [f]-1,2,3,4-tetrahydroisoquinoline.

A second method of making the compounds of Formula 2 is to react thesecondary amine starting materials with an appropriate aldehyde to forman intermediate imine or Schiff's base which can then be reducedcatalytically with hydrogen at a moderate pressure and moderatelyelevated temperature. This process can be represented as follows:##SPC5##

wherein R₃, R₅, R₆ and R₇ have the previously assigned significance.

Representative of the aldehydes which can be used in this process areacetaldehyde, propionaldehyde, butyraldehyde, benzaldehyde,3,4-dimethoxybenzaldehyde, phenylacetaldehyde, diphenylacetaldehyde,p-chlorobenzaldehyde, β,β,β-trifluoropropionaldehyde,3,5-dimethylbenzaldehyde and α-phenylpropionaldehyde.

Some of the Schiff's bases or imines which are produced as intermediatesin the described process areN-ethylidene-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-propylidene-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-benzylidene-7,8-diethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-phenylethylidene-7,8-dipropoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolineand N-diphenylethylidene-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.

Reduction of the intermediate imines can be readily effected bycatalytic hydrogenation at moderate pressures using platinium oxide orpalladium as the catalyst and a suitable liquid carrier such as glacialacetic acid at room temperature or a moderately elevated temperature,such as up to 50° C. Following completion of the hydrogen uptake thereaction mixture can be handled in a conventional way to isolate thedesired tertiary amine. Tertiary amines such as those previously namedherein can be produced by this process.

The tertiary amines provided by this invention having 7,8-dialkoxysubstituents can be converted to the corresponding 7,8-dihydroxycompounds by use of concentrated hydrogen bromide or hydrogen iodide inwater or acetic acid solution to cleave the ether linkages. It ispreferred to use 48 percent hydrogen bromide in water for this cleavage.The reaction proceeds readily at an elevated temperature, and preferablythe reflux temperature. The process can be represented as follows:##SPC6##

wherein R₈ and R₉ are lower alkyl groups and R₃ and R₄ have thepreviously assigned significance.

Some of the compounds which can be produced by cleavage of the alkoxygroups from the 7,8-positions areN-ethyl-7,8-dihydroxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-propyl- 7,8-dihydroxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-phenylethyl-7,8-dihydroxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-benzyl-7,8-dihydroxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-(3,4-dimethoxybenzyl)-7,8-dihydroxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-(3,4,5-trimethoxyphenylethyl)-7,8-dihydroxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-(diphenylethyl)-7,8-dihydroxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-(4-fluorophenylethyl)-7,8-dihydroxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolineandN-(4-methylbenzyl)-7,8-dihydroxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.

The N-substituted-7,8-dihydroxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolines can beconverted to esters by reaction with suitable esterifying agents such asalkanoic acid anhydrides, alkanoyl halides, alkanoic acids andaralkanoyl halides. This process can be represented as follows: ##SPC7##

wherein R₁₀ is a lower alkyl or aryl-lower alkyl group and R₃ and R₄have the previously assigned significance.

Conventional methods can be used to prepare and isolate the esters. Someof the esters which can be produced from the otherwise corresponding7,8-dihydroxy compounds areN-methyl-7,8-diacetoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-propyl-7,8-dipropionyloxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,N-benzyl-7,8-dibenzoyloxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolineandN-diphenylethyl-7,8-diphenylacetyloxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.

The tertiary amines of this invention can be converted to acid additionsalts by contacting the amines with a suitable inorganic acid such ashydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acidor an organic acid such as citric acid, acetic acid, formic acid, malicacid, fumaric acid, succinic acid, benzoic acid and tartaric acid.

Quaternary ammonium salts of the compounds are readily prepared bycontacting the compounds with an alkyl halide or an alkyl sulfate,aralkyl halide or aralkyl sulfate such as methyl chloride, ethylbromide, propyl iodide, benzyl chloride, benzyl sulfate and methylsulfate as well as other compounds known to form quaternary ammoniumsalts with tertiary amines.

The tertiary amines of this invention are useful as neutralizing agentssince they are bases which form salts with acids.

According to a second aspect of the invention, the compounds are alsouseful pharmaceutically. These compounds as the base or acid additionsalt when administered to animals parenterally or orally exert ananti-hypertensive effect. The compounds thus can be used to reduce bloodpressure.

N-(β-3,4-Dimethoxyphenylethyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolinehydrobromide has an ALD₅₀ in mice of 125 to 140 mg/kg i.p. whenadministered as a suspension in 1 percent tragacanth. When administeredat 50 mg/kg i.p. in 1 percent tragacanth to hypertensive rats thefollowing percent change in systolic blood pressure was observed:

    1 hour                  -26.0 ± 4.3                                        2 hours                 -11.3 ± 2.2                                        4 hours                 -6.6 ± 4.2                                         24 hours                -2.8 ± 2.8                                     

N-(β,β-diphenylpropionyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline has an ALD₅₀ in mice of 100 to 180mg/kg i.p. when administered in polyethyleneglycol 400. Whenadministered at 20 mg/kg i.p. in polyethylene glycol 400 to hypertensiverats the following percent change in systolic blood pressure wasobserved:

    1 hour                  -4.4 ± 0.9                                         2 hours                 -6.9 ± 3.0                                         4 hours                 -5.0 ± 1.9                                         24 hours                -2.1 ± 1.3                                     

N-(3,4-dimethoxyphenylacetyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolineas the base has an ALD₅₀ of 160-180 mg/kg i.p. when administered to micein polyethylene glycol 400. When administered at 20 mg/kg i.p. inpolyethylene glycol 400 to hypertensive rats the following percentchange in systolic blood pressure was observed:

    1 hour                  -5.4 ± 1.8                                         2 hours                 -3.9 ± 2.0                                         4 hours                 -6.3 ± 1.1                                         24 hours                -3.1 ± 1.1                                     

N-methyl-7,8-dihydroxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline asthe base in water has an ALD₅₀ in mice of 150 to 200 mg/kg i.p. In theanesthetized normotensive dog a dose of 5 mg/kg i.v. of the base inwater lowered blood pressure 48 percent and after 18 minutes there was a50 percent return to normal blood pressure.

N-(2-methylbutyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolineas the base has an ALD₅₀ in mice of 100-200 mg/kg i.p. when administeredin water. When administered as the base at 20 mg/kg i.p. in water tohypertensive rats the following percent change in systolic bloodpressure was observed:

    1 hour                  -13.1 ± 2.7                                        2 hours                 -8.1 ± 2.8                                         4 hours                 -7.0 ± 1.2                                         24 hours                -1.6 ± 0.8                                     

N-(3,4-dimethoxybenzyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline as the base has an ALD₅₀ of 141 to159 mg/kg i.p. when administered to mice as a suspension in 1 percenttragacanth. When administered at 50 mg/kg i.p. as the base in asuspension in 1 percent tragacanth to hypertensive rats the followingpercent change in systolic blood pressure was observed:

    1 hour                  -8.8 ± 2.9                                         2 hours                 -4.2 ± 3.2                                         4 hours                 -0.7 ± 1.7                                         24 hours                +0.9 ± 3.3                                     

N-(3,3-diphenylpropyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolinehas an ALD₅₀ in mice greater than 1000 mg/kg i.p. when administered as asuspension in 1 percent tragacanth. When administered at 100 mg/kg i.p.in 1 percent tragacanth to hypertensive rats the following percentchange in systolic blood pressure was observed:

    1 hour                  -3.5 ± 3.5                                         2 hours                 -7.9 ± 2.7                                         4 hours                 -6.7 ± 1.6                                         24 hours                -7.0 ± 1.8                                     

N-methyl-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline asthe base has an ALD₅₀ in mice of 100 to 150 mg/kg i.p. when administeredin water. When administered at 50 mg/kg i.p. in water to hypertensiverats the following percent change in systolic blood pressure wasobserved;

    1 hour                  -3.0 ± 5.5                                         2 hours                 -2.9 ± 2.4                                         4 hours                 -6.3 ± 2.2                                         24 hours                -4.6 ± 2.7                                     

N-(3,4-dimethoxybenzoyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline has an ALD₅₀ of 150 to 200 mg/kg i.p.when administered to mice in polyethylene glycol 400. When administeredat 20 mg/kg i.p. in polyethylene glycol 400 to hypertensive rats thefollowing percent change in systolic blood pressure was observed:

    1 hour                  -4.0 ± 3.3                                         2 hours                 -1.4 ± 3.5                                         4 hours                 -3.1 ± 3.2                                         24 hours                +5.6 ± 3.8                                     

The amount of active ingredient administered may be varied; however, itis necessary that the amount of active ingredient be such that asuitable dosage is given. The selected dosage depends upon the desiredtherapeutic effect and on the duration of treatment. Dosages of from 0.1to 25 mg/kg of body weight daily, preferably in divided doses, i.e.,three to four times daily, can be administered.

The active agents of this invention can be administered to animals,including humans, as pure compounds. It is advisable, however, to firstcombine one or more of the compounds with a suitable pharmaceuticalcarrier to attain a satisfactory size to dosage relationship and therebyobtain a pharmaceutical composition.

Pharmaceutical carriers which are liquid or solid can be used. Solidcarriers such as starch, sugar, talc and the like can be used to formpowders. The powders can be used for direct administration or they maybe used to make tablets or to fill gelatin capsules. Suitable lubricantslike magnesium stearate, binders such as gelatin, and disintegratingagents like sodium carbonate in combination with citric acid can be usedto form tablets. Sweetening and flavoring agents can also be included.

Unit dosage forms such as tablets and capsules can contain any suitablepredetermined amount of one or more of the active agents, and they maybe administered one or more at a time at regular intervals. Such unitdosage forms, however, should generally contain a concentration of 0.1to 50 percent by weight of one or more of the active compounds. Unitdosage forms, such as tablets and capsules, can contain about 2 to 300mg of active agent.

A typical tablet can have the composition:

                          Mg                                                      ______________________________________                                        Active agent (1)        100                                                   Starch U.S.P.           57                                                    Lactose U.S.P.          73                                                    Talc. U.S.P.             9                                                    Stearic acid            12                                                    ______________________________________                                    

1. N-(β-3,4-dimethoxyphenylethyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline hydrobromide.

The compounds exhibit both oral and parenteral activity and accordinglythey can be formulated in dosage forms for either oral or parenteraladministration to a patient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, granules and the like.

Liquid dosage forms for oral administration include emulsions,solutions, suspensions, syrups and the like, containing diluentscommonly used in the art, such as water. Besides inert diluents, suchpreparations can also include adjuvants such as wetting agents,emulsifying and suspending agents and sweetening, flavoring andperfuming agents.

Preparations for parenteral administration include sterile aqueous ornon-aqueous solutions. Examples of non-aqueous solvents or vehicles arepropylene glycol, polyethylene glycol, vegetable oils such as olive oiland injectable organic esters such as ethyl oleate. The parenteralpreparations are sterilized by conventional methods.

THE PREPARATION OF STARTING MATERIALS USED IN THIS INVENTION

Intermediate indanaldehydes of the following formula are first prepared:##SPC8##

in which the -CHO is in the 6- or 7-position and R₅ and R₆ have thepreviously assigned meaning. These compounds are prepared by reducing a4,5-dialkoxy-1-indanone to 4,5-dialkoxyindane and then converting thatcompound by means of a Friedel-Crafts reaction to a mixture of4,5-dialkoxy-6-indanaldehyde and 4,5-dialkoxy-7-indanaldehyde. Thisseries of reactions can be represented as follows: ##SPC9##

wherein R₅ and R₆ have the previously assigned significance.

Among the starting materials which can be used in the described sequenceof reactions are 4,5-dimethoxy-1-indanone, 4,5-diethoxy-1-indanone,4,5-dipropoxy-1-indanone and 4-methoxy-5-ethoxy-1-indanone. Thepublication of John Koo in J. Am. Chem. Soc., 75, 1891 (1953) discloses4,5-dimethoxy-1-indanone. Other similar compounds, such as those justnamed, can be prepared by the procedure disclosed therein.

Reduction of the 4,5-dialkoxy-1-indanone can be readily achievedcatalytically using hydrogen and a suitable catalyst such as palladium.The hydrogenation is effected by placing the starting material inglacial acetic acid containing the catalyst and a small amount ofconcentrated hydrochloric acid. The hydrogenation proceeds readily atroom temperature using a hydrogen pressure of about 25 to 100 psig.After hydrogen uptake has ceased the product can be recovered from thereaction mixture by conventional methods.

Some 4,5-dialkoxyindanes which can be produced as described are4,5-dimethoxyindane, 4,5-diethoxyindane, 4,5-dipropoxyindane,4,5-diisopropoxyindane, 4,5-dibutoxyindane and 4-methoxy-5-ethoxyindane.

Formylation of a 4,5-dialkoxyindane according to the method of AlfredRieche et al. in Chem. Ber., 93, 88 (1960) using a Friedel-Craftscatalyst such as stannic tetrachloride, aluminum trichloride or titaniumtetrachloride and α,α-dichloromethyl methyl ether followed by waterleads to the production of a mixture containing4,5-dialkoxy-6-indanaldehyde and 4,5-dialkoxy-7-indanaldehyde. Thepresence of a mixture of isomeric aldehydes is shown by gas-liquidchromatography. A mixture of 4,5-dimethoxy-6- and -7-indanaldehydesformed by the described procedure contains about 75 percent of the7-formyl and 25 percent of the 6-formyl isomers. Obviously, the presenceof other alkoxy groups than the methoxy group could lead to differentamounts of the isomers in the resulting mixture.

The isomeric mixture of aldehydes obtained by the described process isgenerally a liquid. Residual amounts of solvent are removed from theliquid by distillation following which the product is distilled underhigh vacuum to give a pure liquid mixture. Upon cooling, one of theisomeric aldehydes crystallizes from the liquid and is removed byfiltration. Thus, 4,5-dimethoxy-7-indanaldehyde crystallizes and leavesa liquid which is primarily 4,5-dimethoxy-6-indanaldehyde. Fractionaldistillation of the liquid gives the pure 6-formyl isomer.

Some of the separated purified aldehydes which can be prepared by thedescribed method are:

4,5-dimethoxy-7-indanaldehyde,

4,5-diethoxy-7-indanaldehyde,

4,5-dipropoxy-7-indanaldehyde,

4,5-dibutoxy-7-indanaldehyde, and 4-methoxy-5-ethoxy-7-indanaldehyde.

The 7,8-dialkoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolines ofFormula 3 are prepared from the 4,5-dialkoxy-7-indanaldehydes byreacting the aldehyde with a 1-nitroalkane to produce a4,5-dialkoxy-7-nitrovinylindane, chemically reducing the nitrovinylcompound to the corresponding aminoalkyl compound, reacting theresulting amine with formaldehyde to produce a Schiff's base and thentreating the Schiff's base with acid to effect a Pictet-Spengler acidcatalyzed ring closure. This series of reactions can be represented asfollows: ##SPC10##

wherein R₃, R₅ and R₆ have the previously assigned significance.

In effecting the first step of this series of reactions, nitromethane,nitroethane, 1-nitropropane and other such 1-nitroalkanes can be used.

Condensation of the 4,5-dialkoxy-7-indanaldehyde with the nitroalkanecan be readily effected by procedures discussed in Gairaud et al., J.Org. Chem. 18, 1 (1953) and particularly by the use of ammonium acetatein glacial acetic acid at an elevated temperature.

By following the described procedure there is obtained4,5-dimethoxy-7-nitrovinylindane,4,5-dimethoxy-7-(2-nitro-2-methylvinyl)indane,4,5-dimethoxy-7-(2-nitro-2-ethylvinyl)indane,4,5-diethoxy-7-nitrovinylindane, 4,5-dipropoxy-7-nitrovinylindane and4-methoxy-5-ethoxy-7-nitrovinylindane.

The 4,5-dialkoxy-7-nitrovinylindanes are readily reduced chemically bymeans of lithium aluminum hydride in dry ether according to the methodof Marchant et al., J. Chem. Soc. 327 (1956) to produce the desired 4,5l-dialkoxy-7-aminoethylindanes. Some of the compounds which are producedin this way are 4,5-dimethoxy-7-aminoethylindane,4,5-diethoxy-7-(2-aminopropyl)indane,4,5-dipropoxy-7-(2-aminobutyl)indane and4-methoxy-5-ethoxy-7-aminoethylindane.

The 4,5-dialkoxy-7-aminoethylindanes are converted to the Schiff's basesby reaction with formaldehyde using conventional reaction conditions forpreparing Schiff's bases. Some of the compounds so produced areN-methylidene-4,5-dimethoxy-7-(2-aminoethyl)indane,N-methylidene-4,5-diethoxy-7(2-aminopropyl)indane,N-methylidene-4,5-dipropoxy-7-(2-aminobutyl)indane andN-methylidene-4-methoxy-5-ethoxy-7-(2-aminoethyl)indane.

The described Schiff's bases are readily cyclized in aqueous acid, suchas 23 percent hydrochloric acid, at a moderately elevated temperature ofabout 40° to 75° C., to thecyclopentano[f]-1,2,3,4-tetrahydroisoquinolines. The product is readilyrecovered by evaporation of the solvent and acid.

Representative cyclopentano[f]-1,2,3,4-tetrahydroisoquinolines which areproduced as described are7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,7,8-diethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline,7,8-dipropoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline and7-methoxy-8-ethoxy-cyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.

The following examples are presented to illustrate the invention.

EXAMPLE 1N-(2-Methylbutyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolinehydrobromide

To 4.5 g (0.052 mole) of 2-methylbutryaldehyde refluxing in 150 ml ofbenzene was added slowly 4.06 g (0.017 mole) of7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline in 125 ml ofbenzene. After refluxing into a Dean-Stark trap and removing 0.2 ml ofwater, the solvent was removed on an evaporator, the dark red oilremaining was dissolved in 55 ml of glacial acetic acid and hydrogenatedat 45 psi over 0.5 g of PtO₂. The catalyst was removed by filtrationthrough a filter aid, washed with methanol and the acid neutralized with60 g of sodium hydroxide in water. The product was extracted with etherwhile salting out with sodium chloride until no color was given withDragendorf's reagent. Thorough removal of the ether gave 4.98 g ofcherry red oil which was dissolved in anhydrous isopropyl ether andprecipitated by addition of hydrogen chloride gas. The resulting stickysolid was filtered and dried in a vacuum oven, giving a brown mass ofgummy solid which did not crystallize from acetonitrile but came out asan oil when ether was added. The solvent was removed and an attempt tocrystallize from ethanol:ethyl acetate was unsuccessful. Most of thesolvent was removed and the remaining material was dissolved in water.Some black impurity was filtered, and the solution was made basic andextracted with ether. The ether was removed giving a dark red oil whichwas distilled under high vacuum giving a cherry red liquid (2.02 g).This oil was dissolved in benzene and hydrogen bromide gas was added; noprecipitate occurred. The solvent was removed and the yellow oil wasdried overnight which hardened it considerably. This was stirred underanhydrous ether with a stirring bar several times giving a powder. Thispowder was successfully recrystallized from ethylacetate yielding 1.17 g(15.8 percent) of the hydrobromide salt, m.p. 139.5°-142° C.

Anal. Calcd. for C₁₉ H₃₀ BrNO₂ :

C, 59.37; h, 7.86;

n, 3.64; br, 20.78.

Found:

C, 59.17; h, 7.80;

n, 3.56; br, 20.98.

EXAMPLE 2N-Methyl-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolinehydrobromide

After refluxing 2.45 g (0.0105 mole) of7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline in 8.12 mlof 88 percent formic acid and 4.96 ml of formalin for 6 hrs., the acidsolution was washed into a separatory funnel and neutralized withconcentrated ammonium hydroxide. The precipitate was extracted withether and the ether was distilled giving a cherry red oil. Thehydrobromide salt of the oil yielded a solid, after drying, whichrecrystallized well from ethylacetate:absolute ethanol. Tworecrystallizations gave a pure sample, m.p. 228.5-230° C., 1.42 g (41%).

Anal. Calcd. for C₁₅ H₂₂ BrNO₂ :

C, 54.88; h, 6.75;

n, 4.26; br, 24.34.

Found:

C, 55.08; h, 6.74;

n, 4.13; br, 24.41.

EXAMPLE 3N-(β,β-Diphenylpropionyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline

β,β-Diphenylpropionyl chloride was prepared by refluxing 2.45 g (0.016mole) of the corresponding acid with a large excess of SOCl₂ in benzene.After removing the SOCl₂, the resulting acid chloride and 2.45 g (0.0105mole) of 7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline and4.0 ml of triethylamine were refluxed 7-8 hrs. The reaction mixture wascooled, rinsed into a separatory funnel and washed with 150 ml of water,2 × 100 ml of 15 percent sulfuric acid, 2 × 100 ml of 10 percent sodiumhydroxide, and 2 × 100 ml of water. The benzene solution was dried overanhydrous sodium sulfate and then the solvent was thoroughly removed onan evaporator giving a highly viscous oil which was further dried in avacuum oven. The oil did not solidify and all attempts to recrystallizeit failed. Column chromatography on silica gel gave a pure material. Theadsorbent was packed down dry before passing benzene through. Thecompound was added as a solution in benzene and eluted as follows: 5 ×100 ml benzene, 2 × 100 ml 75:25 benzene:chloroform, 2 × 100 ml 50:50benzene: chloroform, 2 × 100 ml 25:75 benzene:chloroform. The amidebegan eluting in the second 100 ml of 25:75 benzene:chloroform. Verysmall quantities of oil came out in earlier fractions but werediscarded. Elution was continued with 800 ml of 25:75 benzene:chloroformof which the first 600 ml contained most of the amide. Removal of thesolvent and thorough drying gave an analytical sample, 1.81 g (27%).

Anal. Calcd. for C₂₉ H₃₁ NO₃ : C, 78.88; H, 7.07; N, 3.17.

Found: C, 78.65; H, 7.10; N, 3.10.

EXAMPLE 4N-(3,3-Diphenylpropyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline

To a slurry of 2.0 g (0.053 mole) of LiAlH₄ in 100 ml of dry ether wasadded 2.96 g (0.0067 mole) ofN-(β,β-diphenylpropionyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolinein 100 ml of ether. After refluxing about 20 hrs., adding 5.0 g offilter aid and decomposing excess hydride with 15 ml of water, the whiteprecipitate was filtered after the ether solution was decanted severaltimes and the precipitate washed with ether. The ether was thoroughlyremoved by distillation. Recrystallization twice from methanol gaveprisms, 1.64 g (54 percent), m.p. 105°-106.5° C.

Anal. Calcd. for C₂₉ H₃₃ NO₂ : C, 81.46; H, 7.77; N, 3.27.

Found: C, 81.55; H, 7.77; N, 3.35.

EXAMPLE 5N-(2,2-Diphenylethyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline

In 150 ml of benzene, 2.12 g (0.009 mole) of7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline and 3.0 g(0.015 mole) of diphenylacetaldehyde were refluxed overnight withremoval of water in a Dean-Stark trap. After removal of the solvent on arotary evaporator, the remaining red oil was dissolved in 75 ml ofglacial acetic acid and hydrogenated over 0.6 g of PtO₂ at 45 psi. Thecatalyst was removed by filtration and the solvent by rotaryevaporation. The resulting oil was treated with dilute hydrochloric acidwhich left a residue. The solution was made basic with sodium hydroxide,an oily precipitate was extracted with ether, the ether was dried oversodium sulfate and removed by distillation giving 3.11 g of anorange-red oil. This oil was dissolved in benzene and reacted withhydrogen bromide gas to give a hard glassy solid upon removal of thebenzene but which did not crystallize after many attempts. The materialwas dissolved in acetonitrile:ethylacetate, the volume was reduced on asteam bath and on cooling a black tarry precipitate occurred. Thesolvent was removed and the free base was extracted after treating theresidue with NaOH. The darkly colored glass obtained was chromatographedon silica gel under the same conditions as in Example 3. A light coloredoil was obtained (in the 25:75 benzene:chloroform fractions) whichcrystallized from methanol giving 1.07 g of prisms (28%) m.p. 100°-102°C.

Anal. Calcd. for C₂₈ H₃₁ NO₂ : C, 81.32; H, 7.55; H, 3.38.

Found: C, 81.34; H, 7.37; N, 3.20.

EXAMPLE 6N-(3,4-Dimethoxyphenylacetyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline

In 75 ml of benzene and 5-6 ml of triethylamine, 2.45 g (0.0105 mole) of7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline and 2.36 g(0.011 mole) of 3,4-dimethoxyphenylacetyl chloride were refluxedovernight. The reaction solution was cooled, washed with 150 ml ofwater, 2 × 100 ml of 10 percent sulfuric acid, 2 × 100 ml of 10 percentsodium hydroxide and finally 150 ml of water. The solvent was removed ona rotary evaporator yielding 4.08 g of a viscous oil which resistedattempts at recrystallization. The oil was purified by columnchromatography similar to the procedure described in Example 3. The oilcame off in the 25:75 benzene:chloroform fractions giving 1.688 g (39percent).

Anal. Calcd. for C₂₄ H₂₉ NO₅ : C, 70.05; H, 7.10; N, 3.40.

Found: C, 69.77; H, 7.13; N, 3.11.

EXAMPLE 7N-(β-3,4-Dimethoxyphenylethyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolinehydrobromide

To 0.5 g (0.013 mole) of LiAlH₄ in anhydrous ether was added dropwise1.27 g (0.0034 mole) ofN-(3,4-dimethoxyphenylacetyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolinein ether. After refluxing 24 hrs., 1.5 g of filter aid was added andexcess LiAlH₄ was decomposed with cooling and very slow addition ofwater (dropwise). The white precipitate was washed with ether followedby decantation several times and then the precipitate was filtered.Removal of the ether on a rotary evaporator gave 1.22 g of light pinkoil. The free amine did not crystallize from methanol, methanol-ether ormethanol-water. The hydrobromide salt was obtained by bubbling hydrogenbromide gas through an ether solution of the amine. After filtering anddrying the precipitate it was recrystallized several times fromacetonitrile giving 1.05 g (71 percent) of white solid, m.p. 234°-236°C.

Anal. Calcd. for C₂₄ H₃₂ NO₄ Br:

C, 60.25; h, 6.74;

n, 2.92; br, 16.70.

Found:

C, 60.00; h, 6.65;

n, 2.78; br, 16.60.

EXAMPLE 8N-(3,4-Dimethoxybenzoyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline

The acid chloride of 3,4-dimethoxybenzoic acid was prepared by thegeneral method described in Example 3 from 2.0 g (0.011 mole) of theacid. After refluxing 2.30 g (0.010 mole) of7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline with theacid chloride and 6 ml of triethylamine in 250 ml of benzene overnight,the reaction mixture was cooled and washed with 2 × 150 ml of water, 2 ×100 ml of 10 percent (V/V) sulfuric acid, 2 × 100 ml of 10 percentsodium hydroxide and finally 2 × 100 ml of water. Removal of the solventgave 4.15 g of an amber oil which possessed a very intense amidecarbonyl absorption in the infrared. This compound was purified bychromatographing twice on silica gel as described in Example 3. By thismethod 1.12 g (29 percent) of very viscous oil was obtained.

Anal. Calcd. for C₂₃ H₂₇ NO₅ : C, 69.50; H, 6.84; N, 3.52.

Found: C, 69.34; H, 6.78; N, 3.40.

EXAMPLE 9N-(3,4-Dimethoxybenzyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolinehydrochloride

To 0.8 g (0.021 mole) of LiAlH₄ in 100 ml of anhydrous ether was added2.25 g (0.0057 mole) ofN-(3,4-dimethoxybenzoyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolinedropwise in 100 ml of ether. After refluxing overnight, 3.0 g of filteraid was added followed by dropwise addition of 5-6 ml of water. Etherwas decanted and the white precipitate was washed with ether severaltimes followed by decantation and finally filtration. Distillation ofthe solvent and drying in an oven yielded 1.85 g of an oil which showedabsence of the carbonyl amide absorption in the infrared. Thehydrochloride salt of the amine was obtained by adding slowly an ethersolution of anhydrous hydrogen chloride to a solution of the amine inanhydrous ether. The salt was washed well with dry ether, filtered andfurther dried giving 2.01 g of material which recrystallized well fromacetonitrile giving 1.36 g (57 percent), m.p. 222.5°-224° C.

Anal. Calcd. for C₂₃ H₂₀ NO₄ Cl:

C, 65.78; h, 7.20;

n, 3.33; cl, 8.44.

Found:

C, 65.88; h, 7.15;

n, 3.43; cl, 8.56.

EXAMPLE 10N-Methyl-7,8-dihydroxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolinehydrobromide

After refluxing 2.0 g (0.0061 mole) ofN-methyl-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolinehydrobromide for 2 hrs. under nitrogen in 25 ml of 48 percent HBr, thesolution was evaporated to dryness on a rotary evaporator. Drying wascompleted in a vacuum oven at about 60° C. Excess acetonitrile wasnecesary to dissolve the product. Upon reducing the volume byapproximately two-thirds crystallization occurred. Recrystallizationfrom acetonitrile and decolorizing with activated charcoal gave 0.775 g(43%), m.p. 242°-244° C.

Anal. Calcd. for C₁₃ H₁₈ NO₂ Br:

C, 52.01; h, 6.04;

n, 4.66; br, 26.61.

Found:

C, 52.14; h, 5.96;

n, 4.72; br, 26.67.

EXAMPLE 11N-Methyl-7,8-diacetoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolinetrifluoroacetate

To 1.0 g (0.0033 mole) ofN-methyl-7,8-dihydroxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolinehydrobromide in 5.0 g (0.083 mole) of glacial acetic acid was added 18 gof trifluoroacetic anhydride. Heat was evolved when the anhydride wasadded accompanied by dissolution of the amine. After stirring 0.5 hr.and refluxing overnight, hydrogen bromide gas was bubbled through thereaction solution for 1 minute and then the volatile components wereremoved on a rotary evaporator. The resulting oil was further dried in avacuum oven at 60°-70° C. in the presence of fresh P₂ O₅ for severaldays. The remaining viscous material was stirred with a glass rod inanhydrous ether until it began to solidify and form small crystals.Recrystallization was successful from ethanol-ether solution. Severalrecrystallizations from this solvent system and a decolorization withactivated charcoal in absolute ethanol gave 0.59 g (42%), m.p.169.5°-172° C.

Anal. Calcd. for C₁₉ H₂₂ NO₆ F₃ :

C, 54.67; h, 5.31;

n, 3.34; f, 13.65.

found:

C, 55.07; h, 5.49;

n, 3.48; f, 13.40.

the Following Examples are Presented to Illustrate the Preparation ofCompounds Used as Starting Materials in the Invention.

EXAMPLE 12 4,5-Dimethoxyindane

A mixture of 52.6 g (0.275 mole) of 4,5-dimethoxy-1-indanone, 3.00 g of5 percent Pd/C, 100 ml of glacial acetic acid and 20 drops of conc. HClwas hydrogenated at 45 psi and room temperature until hydrogen uptakeceased. Following filtration of the used catalyst, two methods were usedto work up the reaction mixture.

A. The acid was neutralized with dilute sodium hydroxide and the productextracted from the aqueous phase with ether. The ether was removed bydistillation and crude 4,5-dimethoxyindane was distilled under reducedpressure, b.p. 133°-135° C (15 mm) yielding 42.0 g (86.4 percent) ofclear liquid. Infrared analysis showed the absence of carbonylabsorption.

B. Most of the acetic acid was removed on the rotary evaporator and theremaining liquid was distilled as before giving 4,5-dimethoxyindane withno significant difference in yield from that obtained in A.

EXAMPLE 13 4,5-Dimethoxy-7-indanaldehyde

To a solution of 10.0 g (0.056 mole) of 4,5-dimethoxyindane, 24.0 g(0.126 mole) of titanium tetrachloride and 104 ml of CH₂ Cl₂ in a 250 ml3-necked flask fitted with a thermometer and condenser and magneticallystirred, 11.0 g (0.096 mole) of α,α-dichloromethyl methyl ether wasadded rapidly dropwise at 0° C. Hydrogen chloride gas was liberatedduring the course of the reaction. After vigorous evolution of HCl hadsubsided, the reaction solution was allowed to slowly warm to roomtemperature and it was stirred for 1 to 2 hours. The solution wasrefluxed for 6 hours, cooled and the reaction mixture was poured over200 ml of ice and water (ether and salt were added at this point toincrease the volume of the organic phase, to invert the two layers andto break emulsions). The organic phase was washed with2 × 100 ml of 8percent NaHCO₃ solution, 1 × 100 ml of water and dried over Na₂ SO₄.After removal of the solvent by distillation, the mixture of aldehydeisomers was distilled under high vacuum (b.p. 115°-126° C; 0.28 mm)giving 10.2 g of the 6- and 7-position aldehydes (88 percent). The7-position aldehyde which crystallized from the liquid was filtered.This process was repeated several times by seeding the filtrate followedby cooling. Gas chromatography showed the white crystalline solid4,5-dimethoxy-7-indanaldehyde to be one component of the two componentmixture. In this way 4.24 g of white solid was obtained, m.p. 41°-44°C., yield 38.5 percent.

Anal. Calcd. for C₁₂ H₁₄ O₃ : C, 69.88; H, 6.84.

Found: C, 70.03; H, 6.66.

EXAMPLE 14 4,5-Dimethoxy-7-nitrovinylindane

To a 100 ml 3-necked round bottom flask fitted with a condenser andthermometer and magnetically stirred, was added 12.97 g (0.063 mole) of4,5-dimethoxy-7-indanaldehyde, 3.00 g (0.039 mole) of ammonium acetate,13.0 ml (0.292 mole) of CH₃ NO₂ and 40 ml of glacial acetic acid. Thismixture was heated for 1 to 2 hours at 112° C. As the reaction solutionbegan to cool the entire solution solidified. After cooling in an icebath and removing the solvent by filtration, the solid4,5-dimethoxy-7-nitrovinylindane was washed with a small volume ofacetic acid giving fine yellow needles (9.55 g) after thorough drying.The filtrate was poured into 300 ml of ice and water from whichprecipitated a slightly gummy, yellow-brown solid. This gave anadditional 1.43 g of crystalline solid after drying and crystallizingfrom methanol giving a total yield of 10.98 g (70 percent). Ananalytical sample melted at 128°- 130° C.

Anal. Calcd. for C₁₃ H₁₅ NO₄ : C, 62.64; H, 6.06; N, 5.62.

Found: C, 62.79; H, 6.12; N, 5.53.

EXAMPLE 15 4,5-Dimethoxy-7-aminoethylindane

To a slurry of 15.0 g (0.395 mole) of LiAlH₄ and 500 ml of anhydrousether in a 5 liter, 3-necked flask fitted with a condenser, mechanicalstirrer and dropping funnel was added 20.0 g (0.084 mole) of4,5-dimethoxy-7-nitrovinylindane dissolved in 2 liters of ether. Theaddition was made over a period of about 4 hours while refluxing theether slurry. When the addition was completed, refluxing was continuedfor an additional 1 to 2 hours. After the addition of 20 g ofdiatomaceous earth and then 70 ml of water slowly, dropwise, withcooling in an ice bath, the supernatant ether was decanted, the saltswere washed with fresh ether several times followed by decantation andfinally filtration. The solvent was removed by distillation and morethoroughly on a rotary evaporator. Cooling in an ice bath gave 15.91 g(90 percent) of 4,5-dimethoxy-7-aminoethylindane as a slightly yellowsolid, m.p., 45°-48° C. High vacuum distillation gave an analyticalsample.

Anal. Calcd. for C₁₃ H₁₉ NO₂ : C, 70.55; H, 8.65; N, 6.32.

Found: C, 70.22; H, 8.49; N, 6.18.

EXAMPLE 16 7,8-Dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinolinehydrochloride

To 11.1 ml of formalin in a round bottom flask heated at 60°-70° C. andmagnetically stirred was added 10.95 g (0.049 mole) of4,5-dimethoxy-7-aminoethylindane (dissolved in 22 ml of methanol)rapidly dropwise. After heating 50 min., the solvent was thoroughlyremoved on a rotary evaporator. The ir spectrum showed absence ofprimary amine stretching vibrations at 3190, 3300, 3370 with a weakeningin intensity of the peak at 1605 cm.sup.⁻¹. TheN-methylidene-4,5-dimethoxy-7-(2-aminoethyl)indane was dissolved in 55ml of 23 percent HCl and heated on a water bath with stirring at 50°-60°C. for 30 minutes. The water-acid solvent was removed on the evaporatorand the residue was dried overnight in a vacuum oven giving a hard solidwhich yielded 11.14 g (84.1%) of7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline whencrystallized from acetonitrileabsolute alcohol, m.p. 232°-235° C. dec.

Anal. Calcd. for C₁₄ H₂₀ NO₂ Cl:

C, 62.33; h, 7.47;

n, 5.19; cl, 13.14.

Found:

C, 62.58; h, 7.36;

n, 5.33; cl, 13.29.

The foregoing detailed description has been given for clearness ofunderstanding only, and no unnecessary limitations should be understoodtherefrom, as modifications will be obvious to those skilled in the art.

What is claimed is:
 1. A compound of the formula ##SPC11##wherein R₁represents hydroxy, alkoxy groups having 1 to 8 carbon atoms oralkanoyloxy groups having 1 to 8 carbon atoms, R₃ represents hydrogen oran alkyl group having 1 to 8 carbon atoms, and R₄ represents an alkylgroup, phenyl-carbonyl, 3,4-dimethoxybenzoyl, phenyl-alkyl,β-3,4-dimethoxyphenylethyl, 3,4-dimethoxybenzyl, benzhydryl-alkyl,alkanoyl, phenyl-alkanoyl, 3,4-dimethoxyphenylacetyl orbenzhydrylalkanoyl groups in which groups represented by R₄ the alkyland alkanoyl groups have 1 to 8 carbon atoms, and nontoxic acid additionsalts thereof.
 2. A compound of the formula ##SPC12##wherein R₁represents hydroxy, alkoxy groups having 1 to 8 carbon atoms oralkanoyloxy groups having 1 to 8 carbon atoms, and R₄ represents analkyl group, phenyl-carbonyl, 3,4-dimethoxybenzoyl, phenyl-alkyl,β-3,4-dimethoxyphenylethyl, 3,4-dimethoxybenzyl, benzhydryl-alkyl,alkanoyl, phenyl-alkanoyl, 3,4-dimethoxyphenylacetyl orbenzhydrylalkanoyl groups in which groups represented by R₄ the alkyland alkanoyl groups have 1 to 8 carbon atoms, and nontoxic acid additionsalts thereof.
 3. A compound according to claim 1 in which R₁ and R₂ areeach the same alkoxy group, R₃ is hydrogen and R₄ is an alkyl group. 4.A compound according to claim 1 in which R₁ and R₂ are each the samealkoxy group, R₃ is hydrogen and R₄ is a phenylalkyl group.
 5. Acompound according to claim 1 in which R₁ and R₂ are each the samealkoxy group, R₃ is hydrogen and R₄ is a benzhydryl-alkyl group.
 6. Acompound according to claim 1 in which R₁ and R₂ are each the samealkoxy group, R₃ is hydrogen and R₄ is an alkanoyl group.
 7. A compoundaccording to claim 1 in which R₁ and R₂ are each the same alkoxy group,R₃ is hydrogen and R₄ is a benzhydryl-alkanoyl group.
 8. A compoundaccording to claim 1 in which R₁ and R₂ are each the same alkoxy group,R₃ is hydrogen and R₄ is a benzoyl group.
 9. A compound according toclaim 1 in which R₁ and R₂ are each hydroxy, R₃ is hydrogen and R₄ is analkyl group.
 10. A compound according to claim 1 in which R₁ and R₂ areeach an alkanoyloxy group, R₃ is hydrogen and R₄ is an alkyl group. 11.A compound according to claim 3 namedN-(2-methylbutyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.12. A compound according to claim 3 namedN-methyl-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.13. A compound according to claim 7 namedN-(β,βdiphenylpropionyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.14. A compound according to claim 5 namedN-(3,3-diphenylpropyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.15. A compound according to claim 5 namedN-(2,2-diphenylethyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.16. A compound according to claim 1 in which R₁ and R₂ are each the samealkoxy group, R₃ is hydrogen and R₄ is a phenylalkanoyl group.
 17. Acompound according to claim 16 namedN-(3,4-dimethoxyphenylacetyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.18. A compound according to claim 1 in which R₁ and R₂ are each the samealkoxy group, R₃ is hydrogen and R₄ is benzoyl.
 19. A compound accordingto claim 18 namedN-(3,4-dimethoxybenzoyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.20. A compound according to claim 4 namedN-(3,4-dimethoxybenzyl)-7,8-dimethoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.21. A compound according to claim 9 namedN-methyl-7,8-dihydroxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.22. A compound according to claim 10 namedN-methyl-7,8-diacetoxycyclopentano[f]-1,2,3,4-tetrahydroisoquinoline.